Liquid oral pharmaceutical compositions of non-steroidal anti-inflammatory drugs

ABSTRACT

A one phase, liquid composition for oral administration comprises a NSAID such as an anthranilic acid derivative plus a di- or triglyceride of a medium chain fatty acid edible oil which has the characteristics of a pharmaceutical solvent carrier as known to those skilled in the art. Other pharmaceutical additives may be optionally added. An additional stipulation is that ethanol or other monohydric alcohol solvents should not be present.

BACKGROUND OF THE INVENTION

Liquid oral pharmaceutical compositions for oral administration havebeen often formulated in the past in vehicles which contain ethanol.Frequently, the compositions thusly prepared do not contain waterbecause of a stability problem, to suppress undesirable organolepticproperties of the composition or to enhance solubility.

Ibuprofen is a non-steroidal anti-inflammatory (analgesic) drug whosefamily is known in the art as NSAID's. It has been on the ethical andproprietary markets for years and is in widespread use. While manydosage unit forms of the compound are on the market, few acceptableoral, one phase liquid forms of ibuprofen have been reported. U.S. Pat.No. 4,684,666, U.S. Pat. No. 3,228,831 and U.K. Patent Specification971,700, are representative of the prior art.

Due to the low solubility of ibuprofen in aqueous vehicles and its poororganoleptic characteristics, certain of us earlier found excellent oraldosage units can be prepared using a vehicle comprising certain edibleoils and absolute ethanol. However, now a new problem has beenidentified.

Ibuprofen, and other NSAID's which have a reactive carboxylic acidmoiety in their chemical structures, have been unexpectedly found toform ethyl ester derivatives in the oral edible oil-alcohol vehicles.

Esterification can reduce the quantity of ibuprofen available forabsorption. The alcohol-oil vehicles remain, however, excellent productsorganoleptically when formulated with NSAID active ingredients. Thefollowing description will describe a solution we have found to thispreviously unrecognized problem in the art.

SUMMARY OF THE INVENTION

This invention comprises a one-phase, liquid pharmaceutical compositionfor oral administration which comprises a NSAID medicament whosemolecular structure contains a reactive carboxylic acid group, asynthetic edible oil glyceride of one or more mid-range fatty acids andoptional pharmaceutical additives with the provision that ethanol is notsubstantially present. Said invention solves the problem described abovewhich is related to the chemical stability of ibuprofen in certain oilyvehicles containing ethanol. This invention also fills the need for anoral solution of ibuprofen or other NSAID's which has an acceptable oralorganoleptic property for patients. Specifically, this inventionprovides a single phase, non-aqueous, non-alcoholic liquid compositionof ibuprofen for oral administration.

The essential ingredients of the pharmaceutical composition of thisinvention are:

(A) About 1% to about 10% w/v of a NSAID such as ibuprofen; and

(B) About 60% to 99% v/v of an edible oil of the group of mid rangefatty acid glycerides; plus the absence of any substantial quantity ofethanol.

This invention depends on the discovery of a small group of liquid,edible liquids which are synthetic or semi-synthetic in nature and inwhich the NSAIDs such as ibuprofen are sufficiently soluble to giveadequate and convenient dosage units for liquid oral dosage, yet do notrequire the presence of alcohol to give good taste and stability.

This invention also provides a method of treating a human with ibuprofenby orally administering to the human, a non-aqueous, alcohol-freepharmaceutical composition of this invention. The pharmaceuticalcomposition of the invention is in the form of solutions which can bemaintained in a single phase over a range of temperatures. Thecomposition has a pleasant taste and can be formulated to avoidirritation of oral mucosa.

DETAILED DESCRIPTION OF THE INVENTION

The one phase, liquid pharmaceutical compositions for oraladministration of this invention comprise a solution of a NSAID, such asibuprofen and an edible oil of the mid range fatty acid glyceride groupin the absence of ethanol. Optional adjuvants, such as flavors, localanesthetics, sweeteners, antimicrobial agents, colorants, antioxidants,or surfactants can be incorporated in the oral compositions of theinvention.

It has been found that aqueous vehicles for NSAID's, especiallyibuprofen, pose unacceptable taste problems or crystal growth during thestorage period. These problems are often present with pharmaceuticalcompositions in aqueous solution or suspension form.

We previously discovered that certain non-aqueous vehicles comprisingcertain edible oils and absolute ethanol plus other optional additivesprovide acceptable solutions for most of the problems associated withoral aqueous compositions of NSAID medicaments. Taste of the non-aqueouscomposition becomes acceptable and irritation of the oral mucosadisappears.

We have now found that when these prior compositions contain ethanol asit was thought necessary, there can be an esterification reactionoccurring between ibuprofen and ethanol. The degree of ester formationincreases with amount of alcohol and storage temperature. (See TableII). Esterification can reduce the availability of the active medicamentto the body or affect the elegance of the pharmaceutical form.

                  TABLE I                                                         ______________________________________                                        Ibuprofen Formulas Used for Chemical                                          Stability Evaluation                                                          Formula #/                                                                    Ingredient                                                                              #229     #265    #241-B #209  #282                                  ______________________________________                                        Ibuprofen 4        4       4      4     4                                     Saccharin 0.02     0.02    0.05   0.3   0.3                                   Menthol   0.24     0.24    0.24   0.24  0.24                                  Eucalyptus Oil                                                                          0.08     0.08    0.08   0.08  0.08                                  Cinnamon  1        --      --     --    --                                    Fruit Mint                                                                              0.7      --      --     --    --                                    Spice Mint                                                                              --       --      0.2    --    --                                    Polysorbate 85                                                                          --       2       --     --    --                                    Ethanol 100%                                                                            --       --      1      10    10                                    "Miglyol 810"*                                                                          100      100     100    100   100                                   q.s.ad                                                                        ______________________________________                                         *Brand name of caprylic/capric triglyceride sold by Dynamit Nobel, West       Germany.                                                                 

                  TABLE II                                                        ______________________________________                                        Chemical Stability of Ibuprofen                                               Formula #/                                                                    Storage Condition                                                                        #229    #265     #241-B                                                                              #209   #282                                 ______________________________________                                        Initial    100%    100%      100%  100%   100%                                1/2 month @75C                                                                           100%    100%     --    80.5%  --                                   1 month @45C                                                                             99.6%   --       --    93.7%  92.5%                                4 months @45C                                                                             98%    --       92.3% --     --                                   ______________________________________                                    

When ibuprofen is dissolved in an edible oil as described hereafter,such as caprylic/capric triglyceride, no evidence of ester formation wasdetected as shown in Table II. Only when ethanol is present is there achemical instability.

Similar problems of ester formation potentially exist for othermedicaments whose structures contain a chemically reactive carboxylicgroup. These drugs are also formulated in the described non-aqueousvehicle containing no ethanol to prevent the ester formation.

Nonsteroidal anti-inflammatory drugs (NSAID's) which have carboxylicfunctional groups and are formulated in these non-aqueous vehiclescontaining no ethanol are as follows:

(1) Salicylic Acid Derivatives--Aspirin, Diflunisal.

(2) Anthranilic Acid Derivatives--Mefenamic Acid, Flufenamic Acid.

(3) Indoleacetic Acid Derivatives--Indomethacin.

(4) Indeneacetic Acid Derivatives--Sulindac.

(5) Pyrroleacetic Acid Derivatives--Tolmetin.

(6) Phenylacetic Acid Derivatives--Ibuprofen, Fenoprofen.

(7) Naphthaleneacetic Acid Derivatives--Naproxen.

The pharmaceutical composition of this invention primarily contains themedicament in a pharmaceutically effective amount. The concentration ofthe medicament in the composition will vary with the medicament, thedesired therapeutic effect and the size of the dosage administered tothe patient. For example, the pharmaceutical composition will containthe medicament in an amount within dosage unit ranges approved by theFood and Drug Administration for over-the-counter sale or within dosageunit ranges listed in the Physician's Desk Reference.

A practical dose range for ibuprofen oral liquid is from about 50 mg toabout 500 mg/5 ml, which corresponds to about 1% to about 10% w/vibuprofen in the composition. This is a teaspoon amount and isadministered orally as needed from 1-6 times daily.

The pharmaceutical composition of the invention can be packaged in unitdosage form or in larger quantities with instructions for obtaining aunit dosage. Usually, as noted above, a dosage unit is contained in ateaspoon quantity of the pharmaceutical composition which isadministered orally as often as needed within the approved daily doserange for the medicament to a patient in need of anti-inflammatoryanalgesic treatment.

The synthetic or semi-synthetic edible oils which are becoming availableto the market as equivalents of vegetable oils are employed in thisinvention as the second essential ingredient. These edible oils includethe "Olestras" (or sugar fatty acid esters) and the preferred "Miglyols"(or fatty acid esters of open chain polyols). Synthetic edible oils arevery useful because of their purity and favorable physicalcharacteristics. Examples of such synthetic oils are the esters andmixed esters of glycerol or propylene glycol (called herein"glycerides"), especially the tri- or diglycerides of medium chain fattycarboxylic acids. More specifically, the C₆ -C₁₂ fatty acid glycerides,and especially the C₈ -C₁₀ fatty acid triglycerides are used. Saidesters must, of course, have satisfactory pharmaceutical and physicalproperties.

The triglycerides of the C₈ -C₁₀ fatty acids of fractionated coconut oilare particularly preferred. A species of this subgroup of edible oils iscommercially available under the trade name "Miglyol", which is atriglyceride of caprylic acid and capric acid with glycerol. Thiscomposition meets the requirements of the British Pharmacopoeia 1980,Addend. 1983, for the monograph "Fractionated Coconut Oil" and of theGerman Pharmacopoeia, DAB 8, for the monograph "Medium ChainTriglycerides". These synthetic oils have been used to prepare otherpharmaceutical products previously but not, to the best of ourknowledge, to prepare one phase oral composition. Palmitic, linoleic,succinic or oleic acid glycerides may also be used if they have theproper solvent properties. The oil is the major ingredient of thedescribed medium and is selected from the range of 60-99% v/v,preferably 90-97% v/v.

The second essential component of the oral dosage units of thisinvention described above, the edible oil, is used as the majoringredient of the composition. It is used to "make-up" the solution tothe proper volume after the therapeutic agent (the NSAID) is mixed withthe optional additives described hereafter.

                  TABLE III                                                       ______________________________________                                        Organoleptic Evaluation of Ibuprofen Formulations                             Formulation     Taste       Irritation                                        ______________________________________                                        4 w/v % Ibuprofen aqueous                                                                     Unacceptable                                                                              Burning sensation                                 solution in Na Salt form    on oral mucosa                                    4 w/v % Ibuprofen aqueous                                                                     Unacceptable                                                                              Burning sensation                                 suspension                  on oral mucosa                                    4 w/v % Ibuprofen in                                                                          Taste improved                                                                            Burning sensation                                 Dehydrated Ethanol/         reduced                                           "Miglyol 810"                                                                 (10/90 v/v %)                                                                 4 w/v % Ibuprofen in                                                                          Taste improved                                                                            Burning sensation                                 "Miglyol 810"               reduced                                           ______________________________________                                    

Irritation of oral mucosa can be entirely eliminated by the use ofeffective amounts of topical oral anesthetics.

It will be understood that nontoxic flavoring agents can be included inthe pharmaceutical compositions to impart a sweet, sour, salty or spicytaste. Examples of flavors are fruit, mint, vanilla, chocolate,cinnamon, licorice, and root flavors. A combination of flavoring agentsis generally effective in masking most unpleasant taste sensations.

The liquid pharmaceutical composition of this invention can also containother adjuvants, such as antimicrobial agents (although these are notusually needed as the vehicle is non-aqueous), colors, antioxidants orsurfactants. Color selection can be made consistent with flavor.Surfactant selection can be made from a group of nonionic-nontoxicsurfactants such as macrogol esters, polysorbates 20, 40, 60, 80 and 85,and mono- and diglycerides of C₁₂ -C₁₈ fatty acids to expedite thedispersion of a pharmaceutical composition in the gastro-intestinaltract. The lowest level of surfactant necessary is usually used. Thesurfactant may also be used to increase the solubility of the NSAIDcomponent in the medium. If the taste of the surfactant isobjectionable, the addition of a sweetening agent such as sucrose orsorbitol has been found to be especially useful.

It will be understood that the pharmaceutical composition can be madetranslucent or even opaque by the addition of adjuvants, provided thatthe amount of the adjuvants does not adversely affect the miscibility ofthe vehicle and medicament, the stability of the pharmaceuticalcomposition, or its organoleptic properties.

The selection of such pharmaceutically acceptable materials and theiruse in the pharmaceutical composition of the invention is within thelevel of skill in the art except where described otherwise herein.

The compositions are prepared by mixing the ingredients in any order.The ingredients can be mixed using conventional manufacturing equipment.Most conveniently, the liquid vehicle is prepared in a mixer and themedication added thereto followed by flavoring additives. A purificationstep can be employed to achieve maximum clarity. The one phase, liquidpharmaceutical composition can then be filled into bottles for sale. Thestability of the ingredients is excellent because of the absence ofwater.

As described above, the present invention is based on discovering aproblem with certain useful one-phase, pharmaceutically elegant oralpharmaceutical compositions which contain nonsteroidal,anti-inflammatory analgesic agents. That problem has now been solved byeliminating one essential element of the prior art vehicle and employingone of a sub group of selected edible oils for the vehicle whichunexpectedly replace the two ingredient vehicles of the prior art.

The following embodients of this invention are designed to illustratethe specific use of this invention, but not to limit the scope ofinvention.

EXAMPLE I LIQUID IBUPROFEN COMPOSITION

The formulations shown in the table below were prepared as follows.First the vehicle was placed in a mixing vessel equipped with a stirrer,and then the medicament and adjuvants were added and mixed with thevehicle. The edible oil was added to bring the volume to 100 ml. Themixture was constantly stirred until a clear solution was obtained. Theclear solution was passed through a 10-micron depth filter and packagedinto proper size glass bottles for sale. One teaspoonful can be orallyadministered to a subject in need of treatment as often as needed and asknown and accepted by the medical art to be available for the individualpatient.

    ______________________________________                                                    #1          #2          #3                                        ______________________________________                                        Ibuprofen U.S.P.                                                                            1      g      4    g    8    g                                  Saccharin N.F.                                                                              0.02   g      0.02 g    0.02 g                                  Menthol U.S.P.                                                                              0.2    g      0.2  g    0.2  g                                  Eucalyptus Oil N.F.                                                                         0.1    ml     0.1  ml   0.1  ml                                 Polysorbate 85                                                                              --            2    g    --                                      "Miglyol 810" q.s. to                                                                       100    ml     100  ml   --                                      "Miglyol 840" q.s. to*                                                                      --            --        100  ml                                 ______________________________________                                         *Brand name of propylene glycol dicaprylate/dicaprate by Dynamit Nobel,       West Germany.                                                            

Each of these preparations is administered orally by from 1-6 teaspoonsper day to a patient in need of anti-inflammatory analgesic activity.

EXAMPLE II LIQUID IBUPROFEN COMPOSITION

The formulations shown in the table below were prepared as follows. Theedible oil, Miglyol 810, was placed in a mixing vessel equipped with astirrer, and then the medicament was added and mixed to make a clearsolution. Adjuvants were then added to the clear ibuprofen solution andthe mixture was homogenized. The formulas contain the medicamentcompletely dissolved in the vehicle. The undissolved excipients provideexcellent taste and mouth feel. One teaspoonful can be orallyadministered to a subject in need of treatment as often as needed and asknown and accepted by the medical art to be available for the individualpatients.

    __________________________________________________________________________                 #4   #5   #6   #7   #8                                           __________________________________________________________________________    Ibuprofen U.S.P.                                                                           4  g 4  g 4  g 4  g 4  g                                         Sodium Saccharin U.S.P.                                                                    0.3                                                                              g --   --   0.3                                                                              g 0.3                                                                              g                                         Saccharin N.F.                                                                             --   0.2                                                                              g 0.3                                                                              g --   --                                           Tandem 552*  1  g 1  g --   --   1  g                                         Arlacel 186**                                                                              --   --   --   0.75                                                                             g --                                           Polysorbate 60 N.F.                                                                        --   --   --   0.25                                                                             g --                                           Polysorbate 85                                                                             --   --   0.5  --   --                                           Sucrose N.F. --   30   --   --   --                                           Mannitol U.S.P.                                                                            --   --   --   30   --                                           Sorbitol N.F.                                                                              20   --   --   --   --                                           Spearmint    --   --   0.3  --   0.5                                          Artificial Fruit Flavors                                                                   0.4  --   --   --   --                                           Peppermint Oil N.F.                                                                        --   0.1  --   0.1  --                                           Cab-O-Sil EH-5***                                                                          0.5  0.5  0.5  0.5  0.5                                          Miglyol 810 q.s.ad                                                                         100                                                                              ml                                                                              100                                                                              ml                                                                              100                                                                              ml                                                                              100                                                                              ml                                                                              100                                                                              ml                                        __________________________________________________________________________     *Brand name of a food grade emulsifier blend of mono and diglycerides and     polysorbate 60 (36%) manufactured by Witco Corporation, Memphis,              Tennessee.                                                                    **Brand name of a emulsifier blend of glycerol monooleate and propylene       glycol manufactured by ICI Americas Inc., Wilmington, Delaware.               ***Brand name of amorphous fumed silica manufactured by Cabot Corp,           Tuscola, Illinois.                                                       

Formula #5 using an excess of sucrose is especially useful andacceptable for pharmaceutical elegance.

What is claimed is:
 1. A single phase, non-aqueous, liquid dosage unitpharmaceutical composition for oral administration comprising atherapeutic but nontoxic dose of a nonsteroidal anti-inflammatory agentwhich is an anthranilic acid derivative and an edible oil comprising anester of glycerol or propylene glycol with 2 or 3 C₆ -C₁₂ fatty acids inthe absence of ethanol.
 2. The pharmaceutical composition of claim 1,wherein the edible oil is caprylic, capric triglyceride,caprylic/capric/linoleic triglyceride, caprylic/capric diglycerylsuccinate, propylene glycol dicaprylate or propylene glycol dicaprate.3. The pharmaceutical composition of claim 2, wherein the amount ofedible oil is about 60% to about 99% v/v.
 4. The pharmaceuticalcomposition of claim 1 in which the non-steroidal anti-inflammatoryagent is mefenamic acid.
 5. The pharmaceutical composition of claim 1 inwhich the non-steroidal anti-inflammatory agent is flufenamic acid. 6.The pharmaceutical composition of claim 1 in which the edible oil iscaprylic/capric triglyceride.
 7. A method of treating a human in need ofanti-inflammatory or analgesic treatment with a non-steroidalanti-inflammatory agent, wherein the method comprises: orallyadministering to said human an oral composition of claim 1.